Hypokalemic paralysis following intramuscular betamethasone injection: A case report and review of literature

Key Clinical Message Acute neuromuscular paralysis is a relatively common condition in emergency rooms (ERs). They can be caused by several reasons, including adverse drug reactions. Betamethasone is a glucocorticoid commonly used for various conditions, such as allergic conditions. One of the rare but known side effects of glucocorticoids is hypokalemia. Rare cases of hypokalemia following high‐ and low‐dose glucocorticoid injections have been reported. This study presents the history of a young, healthy male without significant past medical history who presented with an inability to stand and walk due to four‐limb paralysis (more prominent in the lower limbs) following an intramuscular injection of a 4 mg betamethasone, which was prescribed for the treatment of allergic rhinitis. The patient was stabilized with an intravascular injection of potassium chloride diluted in 1000 mL of normal saline and monitored for 24 h, ruling out any other endocrine condition. Hypokalemia and its severe form are defined as the serum level of lower than 3.5 and 2.5 mEq/Lit, respectively. One of the etiologies of drug‐induced hypokalemic paralysis is systemic glucocorticoid administration. In severe cases, it can cause quadriplegia and other neuromuscular, respiratory, and cardiac complications. Therefore, it is an urgent condition that should be managed carefully. Pregnant women who are receiving these medications are a specific group at risk of hypokalemic paralysis. There are several safer treatments for seasonal allergic rhinitis compared to systemic glucocorticoids, which should be considered by physicians. Moreover, paralysis in patients receiving these medications should be approached attentively since it might be caused by hypokalemia, which can be life threatening if not treated. It is advisable that the blood level of electrolytes, especially potassium, be checked for patients who present with paralysis or weakness after glucocorticoid injections.


| INTRODUCTION
One of the relatively prevalent neuromuscular complaints among patients presenting to the emergency rooms are rapidly progressive neuromuscular paralysis, which can reach its maximum level in less than days or weeks. 1 A wide range of etiologies can cause this condition, and differentiating them is not always straightforward, but differential diagnoses can be limited by considering their specific features. 2These etiologies are generally categorized into four main groups, including: (1) anterior horn cell pathologies; (2) abnormal neuromuscular junction function; 3][4] Infectious, autoimmune, and toxic causes are the most prevalently seen causes of this condition, which can be fatal in some cases.Therefore, the reason should be identified, and an appropriate diagnosis should be initiated as soon as possible. 5ne of the uncommon causes of neuromuscular paralysis is an abnormal serum potassium level. 6otassium is an essential cation in the human body that regulates metabolic cell functions and muscle contractures. 7The abnormally low level of this ion (hypokalemia) is one of the rare but fatal causes of acute neuromuscular paralysis. 8This reversible type of paralysis can be induced by a few identified secondary causes, including druginduced hypokalemia. 9One of the medications that can cause this condition is glucocorticoids. 9Glucocorticoids are widely used for the treatment of various health conditions, such as allergic rhinitis.These medications can cause excessive renal loss of potassium and an increase in NA/K ATPase pumps, which results in the extracellular shift of potassium from skeletal muscles and consequently paralytic symptoms and hyperglycemia-induced insulin secretion. 6his study presents a case of neuromuscular paralysis due to an abnormality in potassium level that manifested with progressive upper and lower limb paralysis, which was more prominent in the lower limbs.To the knowledge of the authors, this presentation of severe hypokalemia in a healthy young man following a low dose of glucocorticoid has rarely been reported in previous literature.

| Case history and examination
The patient was a 34-year-old male who had been brought to the emergency room (ER) with weakness and paralysis of the four limbs, which were more significantly observed in his lower limbs.His symptoms had started 8 h before his presentation and following an intramuscular injection of a 4 mg betamethasone, which had been prescribed due to allergic symptoms.The patient had rhinorrhea, itchy eyes, and pruritis in his face, which were not responsive to nasal corticosteroids.Therefore, an intramuscular injection of betamethasone was prescribed by his general practitioner the day before.The patient had no previous medical or drug history except nasal corticosteroid use due to his seasonal allergic rhinitis.There was no positive history of drug or alcohol abuse.
Based on the patient's ER form, in his physical exam, the patient was conscious and responsive, but he was unable to walk or stand.The vital signs were stable.The cardiovascular examination revealed no abnormalities, and in the neurology examination, except for lower limb paralysis, no significant abnormality was evident.Based on the Medical Research Council (MRC) scoring scale, 10 his lower limbs strength was 1/5 (flicker or trace contraction) bilaterally and in the proximal and distal parts, while his upper limbs strength was 3/5 (active movement against gravity but not resistance) in both proximal and distal parts.He was not able to move his lower limbs actively and was unable to move his hands against resistance.Hypotonia, decreased deep tendon reflexes (DTRs), and flexor bilateral plantar response was also obvious in both lower limbs.Other neurologic examinations, including sensory nerves and sphincter function, higher mental functions, and cranial nerves, were intact.

| Methods
His laboratory data, including complete blood count, comprehensive metabolic panel, blood electrolyte level, arterial blood gas, urine, and blood toxicology tests, including blood and urine alcohol levels, were unremarkable except for his serum potassium level, which was 2.5 mmol/L.Since the patient was a young man and had no renal or gastrointestinal risk factor for hypokalemia, endocrine causes of hypokalemia, such as hyperaldosteronism, 11beta hydroxylase, and 17-alpha hydroxylase deficiency, and less common genetic disorders, namely apparent mineralocorticoid excess (AME) and glucocorticoid resistance syndrome, were considered in the history taking, physical exam, and laboratory evaluations.Plasma aldosterone to plasma renin activity ratio (ARR) for the exclusion of hyperaldosteronism, and 24-h urinary cortisol accompanied by late-night salivary cortisol for ruling out hypercortisolism were obtained.Even though the patient had received a glucocorticoid injection, all mentioned tests were unremarkable.
The patient's cardiac and respiratory functions were immediately monitored in the emergency room.The electrocardiogram showed no abnormality, except premature ventricular contractions (Figure 1).Based on neurological symptoms and hypokalemia (K = 2.5 mmol/L) in the results of blood samples, the intravenous treatment with potassium chloride (40 mmol KCl in 1 L 0.9% NaCl TDS) started immediately.After administration of potassium chloride diluted in 1000 milliliters of normal saline for 6 h, the patient's condition improved gradually, and the muscle weakness improved partially after 6 h.After being observed for 6 h in the ER, the patient was admitted for more observation during the next 24 h in the internal ward.All probable endocrine abnormalities that can cause hypokalemia were ruled out.The symptoms were completely resolved after 24 h of treatment.

| Conclusion
Compatible with the medical team's expectation, the patient's condition remained stable without any further intervention or treatment.The patient was discharged the day after admission after making sure his serum potassium level is within normal range.Outpatient follow-up 3 days, 1 week, and 1 month later showed no abnormality, and all laboratory and imaging studies were normal.The warning signs and probability of recurrence of symptoms and appropriate actions were mentioned to the patient.We advised him to note the event to his family physician in his medical appointments to prevent similar adverse effects occurrences, and this incident was recorded in his electronic file.In the Severe Adverse Reaction form, the name of the patient, his history and physical exam, the medication and the dosage, and the diagnostic and therapeutic interventions and their results were recorded.

| DISCUSSION
Hypokalemia, defined as potassium levels lower than normal range (3.5-5 mEq per L), 11 is mainly caused by decreased potassium intake, increased renal or Electrocardiogram of the patient, when presented to the emergency room, was normal except for occasional premature ventricular contractions (red circle).
gastrointestinal losses, or transcellular shifts into the cells. 12Severe hypokalemia is serum potassium level lower than ≤2.5 mEq/L (Table 1), which can present with different symptoms, including neuromuscular abnormalities (including muscle weakness and cramps), and respiratory or cardiac dysfunction, which might be detected by abnormal electrocardiography. 11,12 The emergence of any of the mentioned conditions necessitates urgent therapeutic intervention. 11Severe neuromuscular paralysis can occur due to hypokalemia caused by various reasons, including transcellular shift, gastrointestinal loss (diarrhea), abnormally high level of serum insulin and catecholamine, renal tubular acidosis (RTA), diabetic ketoacidosis (DKA), and hyperthyroidism.Dengue is another rare but reported cause of neuromuscular paralysis due to hypokalemia. 13ne of the relatively common causes of hypokalemia in young patients are endocrinopathies such as Cushing's syndrome, primary hyperaldosteronism, apparent mineralocorticoid excess (AME), 11-beta hydroxylase and 17-alpha hydroxylase deficiency, and glucocorticoids resistance syndrome. 11Patients with any sign or symptom suspicious for these diagnoses should be evaluated by plasma aldosterone to plasma renin activity ratio (ARR) for the exclusion of excessive aldosterone production.5][16][17] Chronic alcohol use can also be a reason for hypokalemia and should be ruled out.This association is not well understood, but it has been attributed to more than normal gastrointestinal loss due to diarrhea and vomiting, excessive renal loss caused by renal tubular acidosis, and concomitant hypomagnesemia. 18The mechanism of hypomagnesemia-induced hypokalemia is attributed to the increased movement of potassium to the extracellular space and distal tubule potassium excretion. 191][22][23][24] There are various mechanisms for medications to cause hypokalemia, including increasing renal loss, which is the main mechanism seen in glucocorticoids, and antibiotic-induced hypokalemia. 7lucocorticoid agents are the known but rarely reported cause of hypokalemia via the extracellular potassium shift pathway.Increased Na+/K + -ATPase levels in skeletal muscle cells caused directly by glucocorticoids, along with mediating hyperglycemia with consequent insulin secretion 25 and hypokalemia due to renal losses 26 are the main mechanisms of glucocorticoids-induced hypokalemia.Betamethasone-induced hypokalemia was reported in 2011 in a pregnant woman by Corey M. Teagarden. 9In this case, a 23-year-old woman, gravida 3 para 2, presented at 32 weeks of gestation with leaking fluid and the diagnosis of preterm premature rupture of membranes (PPROM).She received two doses of 12 mg IM betamethasone 24 h apart, experiencing proximal limb muscle weakness after the first dose and exacerbation of symptoms and extension of that to neck and hip muscles after the second dose.The potassium was measured as 1.6 mEq/L.This condition is managed with intravenous potassium chloride. 9Severe hypokalemia is mainly treated by IV potassium chloride (10-20 mEq/h) diluted in 1000 mL of normal saline.The level of potassium, electrocardiogram changes, the way of infusion, which should be central for >10 mEq/h, and parallel oral potassium treatment should be considered during treatment. 22This study presents other case report literatures about hypokalemia in more detail (Table 2).
Seasonal allergic rhinitis (SAR) is an IgE-mediated, inflammatory process that is mainly triggered by environmental allergens.This condition involves the nasal mucosa, and the typical hint of its diagnosis is the presence of inflammatory cells within the mucosa and submucosa. 27The manifestation of this condition is mainly seen as nasal discharge, nasal itching, sneezing, and nasal obstruction. 28,29The treatment of this condition is based on four main pillars: education of patients and their caregivers, avoidance of allergens and irritants, medications, and allergen immunotherapy in cases that are not responsive to previous steps. 27][23] T A B L E 2 Review of literatures for drug-induced hypokalemia.

Symptoms and signs Laboratory data Treatment and progression
Teagarden C, et al. glucocorticoid agents are one of the most effective agents in SAR treatment, there are several safer and more sufficient therapeutic options for the treatment of SAR, which include nasal corticosteroids, oral and nasal antihistamines, and topical ophthalmic products. 30,31

| Clinical key point
Considering safety concerns related to the side effects of IM and IV injections of corticosteroids is an essential part of their prescription for any medical condition, and a history of any previous reaction should be obtained from the patient.There are several nonmedical and medical options for the treatment of SAR, and systemic glucocorticoids should not be considered the first line and routine treatment.Patients presenting with symptoms suspicious of hypokalemia, such as paralysis, weakness, and abnormal heart rhythm and ECG, should be evaluated for electrolyte levels of blood, especially potassium, as soon as possible.These patients' medical and drug histories should be obtained cautiously due to the necessity of ruling out endocrine disease or side effects of medications.Moreover, treatment of severe hypokalemia needs immediate action.However, the level of potassium should not rise excessively and without considering the method of IV administration, changes in potassium level, and cardiac function.
mEq/L Changes in electrocardiogram such as STsegment depression, U-wave elevation, and T-wave inversion, arrhythmias, and paralysis